Imidazoline-1 Receptor Ligands as Apoptotic Agents: Pharmacophore Modeling and Virtual Docking Study

Author(s): Katarina Nikolic, Nevena Veljkovic, Branislava Gemovic, Tatjana Srdic-Rajic, Danica Agbaba.

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 16 , Issue 4 , 2013

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Abstract:

The group of imidazoline-1 receptors (I1-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I1-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I1-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I1-IR agonist), moxonidine (moderate I1-IR agonist), and efaroxan (I1-IR partial agonist) on cancer cell line (K562) expressing Nischarin. The Nischarine domains mapping was performed by use of the Informational Spectrum Method (ISM). The 3DQuantitative Structure-Activity Relationship (3D-QSAR) and virtual docking studies of 29 I1-IR ligands (agonists, partial agonists, and antagonists) were carried out on I1-IR receptors binding affinities. The 3D-QSAR study defined 3Dpharmacophore models for I1-IR agonistic and I1-IR antagonistic activity and created regression model for prediction of I1-IR activity of novel compounds. The 3D-QSAR models were applied for design and evaluation of novel I1-IR agonists and I1-IR antagonists. The most promising I1-IR ligands with enhanced activities than parent compounds were proposed for synthesis. The results of 3D-QSAR, ISM, and virtual docking studies were in perfect agreement and allowed precise definition of binding mode of I1-IR agonists (Arg 758, Arg 866, Val 981, and Glu 1057) and significantly different binding modes of I1-IR antagonists or partial I1-IR agonists. The performed theoretical study provides reliable system for evaluation of I1-IR agonistic and I1-IR antagonistic activity of novel I1-IR ligands, as drug candidates with anticancer activities.

Keywords: Apoptotic activity, I1-imidazoline receptor, I1-IR agonist, I1-IR antagonist, pharmacophore modeling, structure activity relationship, virtual docking, Nischarin Protein Modeling, Density Functional Theory, Imidazoline-1 Receptors, α2-adrenenoceptors.

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Article Details

VOLUME: 16
ISSUE: 4
Year: 2013
Page: [298 - 319]
Pages: 22
DOI: 10.2174/1386207311316040004
Price: $58

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